Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip

BMC Medical Genetics

Research Article

Essa Alharby¹  Sulman Basit¹  Alia M. Albalawi¹  Khalid I. Khoshhal² 

[1] Centre for Genetics and Inherited Diseases, Taibah University, 30001, Almadinah Almunawwarah, Saudi Arabia;Department of Orthopedic Surgery, College of Medicine, Taibah University, Almadinah Almunawwarah, Saudi Arabia;

关键词: ATP2B4;    Developmental dysplasia of the hip;    Exome sequencing;    Perlecan;    HSPG2;   

DOI  :  10.1186/s12881-017-0393-8

 received in 2016-10-30, accepted in 2017-03-07,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundDevelopmental dysplasia of the hip (DDH) is a common pathological condition of the musculoskeletal system in infants which results in a congenital and developmental malformation of the hip joint. DDH is a spectrum of pathologies affecting the infant hip ranging from asymptomatic subtle radiographic signs through mild instability to frank dislocations with acetabular dysplasia. A Saudi family with three affected individuals with DDH was identified and genetic analysis was performed to detect the possible genetic defect(s) underlying DDH in the affected members of the family.MethodsWe performed whole genome genotyping using Illumina HumanOmni 2.5 M array and whole exome sequencing (WES) using Nextera Rapid capture kit and Illumina NextSeq500 instrument in four individuals of a family with DDH.ResultsSNP data analysis did not identify any runs of homozygosity and copy number variations. Identity-by-descent (IBD) analysis on whole genome genotyping data identified a shared haplotypes on chromosome 1 in affected individuals. An analysis of the WES data identified rare heterozygous variants in HSPG2 and ATP2B4 genes in the affected individuals. Multiple prediction software predicted that the variants identified are damaging. Moreover, in silico analysis showed that HSPG2 regulates ATP2B4 expression using a variety of transcription factors.ConclusionOur results indicate that there might be a functional epistatic interaction between HSPG2 and ATP2B4, and DDH in the family studied is due to a combined effect of both variants. These variants are also present in the asymptomatic mother suggesting that the variants in HSPG2 and ATP2B4 are incompletely penetrant. This study provides the first evidence of digenic inheritance of DDH in a family and extends the spectrum of genetic heterogeneity in this human disorder.

【 授权许可】

CC BY   
© The Author(s). 2017